Adoptive Cell Therapy Aims to Improve Outcomes in Metastatic Melanoma

Amod Sarnaik, MD

Lifleucel (LN-144), a tumor-Infiltrating lymphocyte (TIL) therapy that uses the patient’s own immune cells to recognize and potentially kill cancer cells, is being investigated in patients with metastatic melanoma.

The phase 2, international, singlearm, C-144-01 trial (NCT02360579) was developed to assess the efficacy and safety of lifileucel therapy in patients with stage IIIc or IV unresectable or metastatic melanoma who have progressed after at least 1 prior systemic treatment including a PD-1 immune checkpoint inhibitor (ICI) and, if BRAF mutation–positive, BRAF or BRAF/MEK inhibitor therapy.¹

Patients with metastatic melanoma who have progressed on or are refractory to ICIs or BRAF and MEK inhibitors currently have no approved agents in later lines of therapy. This patient population has demonstrated poor response to either retreatment with ICIs or chemotherapy with an overall response rate between 4% to 10% and a median overall survival of approximately 7 to 8 months.²

Building on Historical Data

First examined at the National Cancer Institute (NCI), adoptive cell therapy using a patient’s TILs has demonstrated antitumor activity with durable long-term responses in a heavily pretreated population.³ Steven A. Rosenberg, MD, PhD, a 2013 Giants of Cancer Care^® award winner, pioneered the technology at the NCI, where he is chief of the surgery branch.

“Adoptive cell therapy has been around for more than a decade. Dr Rosenberg discovered that when you resect tumors out of patients, you can find residual tumor-reactive T cells within the tumor,” Amod Sarnaik, MD, the principal investigator for the lifileucel trial, said in an interview with OncLive^®. “There has been a lot of effort put forth to try to operationalize that phenomenon as a potential treatment. After explanting the tumor one can actually artificially manipulate it in a laboratory environment in ways that cannot be done while trying to treat the tumor when it is in situ.”

Investigators hypothesized that adoptive cell therapy would translate to clinical efficacy through the selection of the most highly avid antitumor lymphocytes, expansion of these lymphocytes ex vivo in the absence of endogenous regulatory mechanisms, and the manipulation of the host immune environment using lymphodepletion in their absence.⁴ Over the course of several years of research, a study evaluating 93 patients with measurable metastatic melanoma across 3 clinical trials using lymphodepleting preparative regimens reported durable outcomes.⁵

“At the NCI they were able to tweak the treatment to get a pretty good response rate. At the time they reported a 56% overall response rate, and this included a 22% complete response rate that was durable for many years⁵,” noted Sarnaik, a surgical oncologist in the Department of Cutaneous Oncology, the Immunology Program, and the Melanoma Center of Excellence at Moffitt Cancer Center in Tampa, Florida.

Despite data demonstrating promise with durable responses, the shortcomings of the early trials boiled down to the nature of the disease and the prolonged manufacturing time. Rosenberg et al estimated that about 5% of patients develop complications of tumor growth during the 4 to 6 weeks of cell preparation that preclude treatment.⁶ These were 2 areas in which C-144-01 investigators sought improvement.

Design Changes Generate Outcomes

The ongoing C-144-01 study, which is no longer recruiting participants, consists of 4 cohorts. In cohort 1, patients received “first-generation” lifileucel therapy that hadnot been cryopreserved. In cohorts 2 through 4, participants were treated with “second-generation” cryopreserved lifileucel therapy (Figure).¹ All 3 primary cohorts are fully enrolled, with cohort 3 serving as an experimental retreatment subgroup for patients in cohort 2 who experience progression following TIL therapy. Cohort 4 has been adapted so that all patients with BRAF mutation–positive diease have been previously treated with a BRAF or BRAF/MEK inhibitor.

Figure. Lifileucel Trial in Metastatic Melanoma¹

The cryopreservation cohorts were introduced to further evaluate the efficacy of lifileucel under a shortened TIL manufacturing process.⁷ Iovance Biotherapeutics, which is developing lifileucel, was able to design a treatment process that shortened cell preparation from 7 to 8 weeks to a 22-day period from surgery until infusion, Sarnaik said.

To receive lifileucel therapy, patients were required to have at least 1 tumor lesion or aggregate of lesions 1.5 cm or greater in diameter available for resection for TIL generation. Upon resection, the harvested tumor samples are sent to a centralized manufacturing facility where the TILs are extracted and multiplied in a laboratory until billions of them are obtained. Prior to adoptive cell infusion, patients undergo chemotherapy-induced lymphodepletion to enhance the persistence of the transferred cells and improve the anticancer effect.

Following the completion of the manufacturing process, the expanded TILs are cryopreserved and shipped back to the patient’s site of treatment. The TILs are then administered via intravenous infusion to the patient as lifileucel. Immediately following infusion, patients receive up to 6 doses of interleukin 2 (IL-2) to support the growth and activation of the TILs in the patient, and to augment the anticancer activity of the TIL therapy.^1,4

Data from cohort 2 were presented by Sarnaik at the 2020 American Society of Clinical Oncology Virtual Scientific Meeting. Sixty-six patients with high baseline tumor burden who had received a mean of 3.3 prior therapies underwent treatment with lifileucel. After a median study follow-up of 18.7 months, the objective response rate was 36.4%, with 33.3% of patients having a partial response and 3.0% having a complete response.⁷

“The response rate was a little higher than what I expected in this cohort,” said Sarnaik. In terms of how this therapy stacks up against comparators, Sarnaik noted that the response rate comes close to what would be expected with frontline anti–PD-1 therapy. “The response is around 30% to 40% with PD-1 antibodies, so it’s a bit surprising that a second- or even third-line therapy like this would have a response rate that comes close to that response rate.”

The data further demonstrated that 43.9% of patients had stable disease, which translated into a disease control rate of 80.3%, whereas 13.9% experienced progressive disease. The median duration of response was not reached (range, 2.2 to 26.9 + months).⁷

The safety profile for lifileucel was consistent with the disease setting, lymphodepletion, and the IL-2 regimens used, Sarnaik said in his presentation. He noted that the frequency of adverse events decreased over time.

All participants reported at least 1 treatment- emergent adverse event (TEAE) of any grade, including 97.0% with a TEAE of grade 3 or 4 severity. The most frequently reported grade 3 or 4 TEAEs include thrombocytopenia (81.8%), anemia (56.1%), and febrile neutropenia (54.5%). Additionally, 2 patients died during the study, 1 due to an intraabdominal hemorrhage possibly associated with the therapy and the other as a result of acute respiratory failure not attributed to the study therapy.

Findings from cohort 4 of the trial will be used to support drug approval filings with the FDA and European regulatory agencies. “There were a couple of patients in cohort 2 who had had tumors that were BRAF V600 mutated and were not previously treated with the BRAF or BRAF/MEK inhibitor. So, all patients in cohort 4 whose tumors were BRAF V600 mutated were treated previously and either progressed or were refractory,” Sarnaik explained.

Early data from cohort 4 (n = 68) showed an overall response rate of 32.4% by investigator assessment at a median of 5.3 months’ follow-up. Iovance stated that updated findings will be presented at upcoming medical meeting and that the developer plans to submit a biologics licensing application for lifileucel in late 2020.⁸

Treating a Challenging Population

In reviewing the data from the American Society of Clinical Oncology meeting, Sarnaik noted that 44% of patients have liver and brain metastases upon diagnosis.⁷ “These patients uniformly presented with advanced disease; they were not selected for ‘good tumor biology.’ After tumor progression on anti–PD-1 antibody- based therapy, which all but 1 patient had, unfortunately the disease biology is automatically selected to be unfavorable,” he said.

Getting patients to therapy is another hurdle, which Sarnaik notes could have been a barrier to enrollment had the trial not taken place both in the United States and in Europe. As for this therapy becoming a widely available treatment, the requirements remain a hurdle for a majority of patients with advanced disease and comorbidities. “It’s a bit more difficult to recruit patients to an adoptive cell therapy trial as opposed to a systemic intravenous therapy of so-called off-the-shelf drugs and it’s for a couple of reasons,” he said. “The first is that in terms of patient selection one has to take into account that the tumor harvest requires surgery and a clinician would not perform an elaborate surgical resection with significant adverse events that could delay treatment.”

Further, patients with advanced melanoma do not receive therapeutic benefit until the TIL therapy is administered. “So, to have a surgical resection that has a high morbidity would not really be palatable to the patient nor to the recruiting investigator,” Sarnaik added. Despite the best efforts of drug developers to speed up manufacturing processes, patients may die before treatment is ready.

One upside to the therapy, however, is the single treatment cycle. “One point that is unique to this treatment, and that may be a little more attractive to the patients, is that it is a single treatment and does not involve repetitive cycles. So, if the patients are able to commit to the waiting period from screening to TIL harvest, and then the 22 days until administration, after that 1 single cycle there is no further active treatment. I think that is to the patients’ advantage,” Sarnaik concluded.

References

1. Study of Lifileucel (LN-144), autologous tumor infiltrating lymphocytes, in the treatment of patients with metastatic melanoma (LN-144). ClinicalTrials.gov. Updated January 21, 2020. Accessed June 23, 2020. https://clinicaltrials.gov/ct2/show/NCT02360579 
2. Sarnaik A, Khushalani NI, Chesney JA. Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies. J Clin Oncol. 2020;38(suppl 15):10006. doi:10.1200/JCO.2020.38.15_suppl.10006
3. Immunotherapy for metastatic melanoma. Iovance Biotherapeutics. Accessed June 23, 2020. https://www.iovance.com/clinical/c-144-01-metastatic-melanoma/ 
4. Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26(4):332-342. doi:10.1097/00002371-200307000-00005
5. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550-4557. doi:10.1158/1078-0432.CCR-11-0116
6. Iovance reports pivotal cohort 4 data for tumor infiltrating lymphocyte (TIL) therapy lifileucel from C-144-01 clinical study in advanced melanoma. News release. GlobeNewswire; May 27, 2020. Accessed June 23, 2020. https://www.globenewswire.com/news-release/2020/05/27/2039716/0/en/Iovance-Reports-Pivotal-Cohort-4-Data-for-Tumor-Infiltrating-Lymphocyte-TIL-Therapy-Lifileucel-from-C-144-01-Clinical-Study-in-Advanced-Melanoma.html